Susan X. N. Lin

Objective: Variants in GABRG2 , encoding the γ2 subunit of the γ‐aminobutyric acid type A receptor, are linked to epilepsy phenotypes of varying severity, with gain‐of‐function (GoF) variants associated with the more severe phenotypes than loss‐of‐function variants. Here, we provide a comprehensive analysis of the early clinical features, motor, language, and eating abilities, and structural consequences of the recurrent GABRG2 p.(Ala106Thr) GoF variant, aiming to refine genotype–phenotype correlations and deepen the understanding of GoF‐associated GABRG2 disorders. Methods: Individuals were recruited through international collaborations, literature review, and patient advocacy groups. Clinical data were collected via standardized interviews and physician reports. Functional effects were assessed using electrophysiological recordings. Structural modeling was performed using homology‐based approaches to evaluate conformational changes. Results: We collected 23 unrelated individuals harboring the GABRG2 p.(Ala106Thr) variant. Symptoms began with early dysphagia (median onset age = 1 month), hypotonia, seizures (median onset age = 2 months), and hyperkinetic movement disorders (median onset age = 3 months). Epilepsy was present in 91% of the individuals, 71% featuring a developmental and epileptic encephalopathy; 33% of the individuals with epilepsy achieved seizure freedom during the follow‐up. All individuals exhibited moderate to severe cognitive/neurodevelopmental impairment, with profound deficits in motor, language, and other domains. Functional analysis confirmed a GoF effect of the p.(Ala106Thr) variant. By contrast, another variant affecting the same residue, p.(Ala106Pro), which is observed in population databases, was functionally characterized as neutral. Structural modeling indicated that the p.(Ala106Thr) variant may enhance receptor gating by facilitating a hydrogen bond between the extracellular and transmembrane domains, a mechanism not observed with the p.(Ala106Pro) variant. Significance: Although some individuals exhibited severe developmental impairment without epilepsy, our findings demonstrate that the recurrent GABRG2 p.(Ala106Thr) GoF variant is consistently associated with a severe neurodevelopmental phenotype. Despite its profound clinical impact, in silico tools consistently predict this variant as benign, highlighting a critical gap in current predictive models.

Normal brain function requires a tightly regulated balance between excitatory and inhibitory neurotransmissions. γ‐Aminobutyric acid type A (GABA_A) receptors represent the major class of inhibitory ion channels in the mammalian brain. Dysregulation of these receptors and/or their associated pathways is strongly implicated in the pathophysiology of epilepsy. To date, hundreds of different GABA_A receptor subunit variants have been associated with epilepsy, making them a prominent cause of genetically linked epilepsy. While identifying these genetic variants is crucial for accurate diagnosis and effective genetic counselling, it does not necessarily lead to improved personalised treatment options. This is because the identification of a variant does not reveal how the function of GABA_A receptors is affected. Genetic variants in GABA_A receptor subunits can cause complex changes to receptor properties resulting in various degrees of gain‐of‐function, loss‐of‐function or a combination of both. Understanding how variants affect the function of GABA_A receptors therefore represents an important first step in the ongoing development of precision therapies. Furthermore, it is important to ensure that functional data are produced using methodologies that allow genetic variants to be classified using clinical guidelines such as those developed by the American College of Medical Genetics and Genomics. This article will review the current knowledge in the field and provide recommendations for future functional analysis of genetic GABA_A receptor variants. image